Using Genome-Wide Association Studies to Identify Genes Important in Serious Adverse Drug Reactions

Genome-wide association (GWA) studies have detected novel associations for serious, idiosyncratic, adverse drug reactions including liver toxicity, hypersensitivity, skin rash, and myotoxicity. Human leukocyte antigen (HLA) genotype has been established as an important predictor of susceptibility to drug-induced liver injury, including injury with some drugs where immune-related toxicity was not suspected previously. Similarly, GWA studies have shown a key role for HLA genotype in susceptibility to carbamazepine-related skin rash and hypersensitivity. HLA genotype is not a risk factor for all forms of drug-induced liver injury or for myotoxicity or cardiotoxicity. For simvastatin-related myotoxicity, a strong association with SLCO1B1, which encodes the hepatic statin uptake transporter, has been detected. Genome-wide studies have not yet found clear associations for drug-induced cardiotoxicity, but for bisphosphonate-induced necrosis of the jaw, polymorphisms in the cytochrome P450 CYP2C8 may predict susceptibility. Larger GWA studies and whole-genome sequencing may provide additional insights into all these toxicities.